Endothelial Dysfunction and Elevation of S -Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice

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Abstract
—Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S-adenosylmethionine (SAM) and its metabolite S-adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS+/–) and wild-type (CBS+/+) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS+/– mice compared with CBS+/+ mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L; PPPP+/– mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS+/– mice, and correlations were observed between plasma total homocysteine and SAH in liver (r=0.54; Pr=0.67; P+/– mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.

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